| Design and synthesis of novel indole beta-diketo acid derivatives as HIV-1 integrase inhibitors. | |
| | |
MedLine Citation:
|
PMID: 15456274 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN). A plethora of diketo acid-containing compounds have been claimed in patent literature without disclosing much biological activities and synthetic details (reviewed in Neamati, N. Exp. Opin. Ther. Pat. 2002, 12, 709-724). To establish a coherent structure-activity relationship among the substituted indole nucleus bearing a beta-diketo acid moiety, a series of substituted indole-beta-diketo acids (4a-f and 5a-e) were synthesized. All compounds tested showed anti-IN activity at low micromolar concentrations with varied selectivity against the strand transfer process. Three compounds, the indole-3-beta-diketo acids 5a and 5c, and the parent ester 9c, have shown an antiviral activity in cell-based assays. We further confirmed a keto-enolic structure in the 2,3-position of the diketo acid moiety of a representative compound (4c) using NMR and X-ray crystallographic analysis. Using this structure as a lead for all of our computational studies, we found that the title compounds extensively interact with the essential amino acids on the active site of IN. |
| | |
Authors:
|
Mario Sechi; Massimiliano Derudas; Roberto Dallocchio; Alessandro Dessì; Alessia Bacchi; Luciano Sannia; Fabrizio Carta; Michele Palomba; Omar Ragab; Carney Chan; Robert Shoemaker; Shizuko Sei; Raveendra Dayam; Nouri Neamati |
Related Documents
:
|
1109574 - Aminobenzoic acid diuretics. 7. 3-substituted 4-phenyl-, 4-arylcarbonyl-, and 4-arylmet... 1243074 - Hypolipemic activity of clofibrate-related compounds. 17616114 - Synthesis and biological activity of azido analogues of 5,6-dimethylxanthenone-4-acetic... 15789554 - Solid-phase synthesis of model libraries of 3alpha,17beta-dihydroxy-16alpha-(aminoethyl... 22530924 - Attachments of sulfonic acid group in the interlayer space of a layered alkali silicate... 11456384 - The role of n-6 polyunsaturated fat in stable asthmatics. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Journal of medicinal chemistry Volume: 47 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2004 Oct |
Date Detail:
|
Created Date: 2004-09-30 Completed Date: 2004-11-10 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
|
Languages: eng Pagination: 5298-310 Citation Subset: IM |
Affiliation:
|
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy. mario.sechi@uniss.it |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Cells, Cultured Crystallography, X-Ray Drug Design HIV Integrase / chemistry, metabolism* HIV Integrase Inhibitors / chemical synthesis*, chemistry, pharmacology HIV-1 / drug effects* Humans Indoles / chemical synthesis*, chemistry, pharmacology Keto Acids / chemical synthesis*, chemistry, pharmacology Magnetic Resonance Spectroscopy Models, Molecular Molecular Structure Solutions Structure-Activity Relationship T-Lymphocytes / virology |
| Grant Support | |
ID/Acronym/Agency:
|
N01 CO 12400/CO/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/HIV Integrase Inhibitors; 0/Indoles; 0/Keto Acids; 0/Solutions; EC 2.7.7.-/HIV Integrase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Structure-activity relationship of heterobase-modified 2'-C-methyl ribonucleosides as inhibitors of ...
Next Document: Rapid prediction of chemical metabolism by human UDP-glucuronosyltransferase isoforms using quantum ...